Composition and methods of treating acne and photoaging

ABSTRACT

Pharmaceutical compositions comprising a first anti-acne compound, a second anti-acne compound, and an anti-photoaging compound are described. Methods for the treatment of acne and photoaging using the compositions are also described.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/037,703, filed Jul. 17, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/223,229, filed Jul. 29, 2016, now U.S. Pat. No.10,064,884, which issued on Sep. 4, 2018 and claims priority to U.S.Patent Application No. 62/199,092, filed Jul. 30, 2015, each of which isincorporated herein by reference in its entirety.

TECHNICAL FIELD

The present invention relates generally to the field of dermatology andmore specifically to compositions and methods for the treatment of acneand photoaging.

BACKGROUND

Acne occurs in greater than 90% of the population at some point in theirlives. Although it is primarily considered a disorder of the teenageyears, many people (and especially females) suffer from acne duringadulthood. Acne (also known as acne vulgaris) is a long-term skincondition that is caused by: 1) plugging of hair follicles by abnormallykeratinized cells, 2) microbial colonization of the follicle, 3)inflammation, and 4) increased oil production associated withcirculating hormones.

Photoaging occurs naturally as our skin is exposed to the sun'sultraviolet rays, and the first signs of photoaging (including finewrinkles and hyperpigmentation) typically appear between the ages of 20and 35. While sun protection is key to minimizing photoaging, there arealso various topical treatments which have proven to be efficacious fortreating and preventing photoaging.

The desire to treat acne commonly coexists with the desire to treatand/or prevent photoaging. While the application of multipledermatologic products is an option currently employed by many patients,the existence of a single, efficacious, stable composition would offerbenefits in convenience and adherence.

There are numerous difficulties in formulating a single, efficacious,stable composition to treat or prevent acne and photoaging.

First, the successful treatment of acne alone typically involves usingtwo different agents with complementary mechanisms of action. The mostcommon categories are comedolytics (which help keratinization and thusprevent clogged pores) and antimicrobials (which generally target theacne-causing bacterium Propionibacterium acnes or P. acnes). So, thesuccessful treatment of acne and photoaging together would typicallyrequire three or more active ingredients, which may require differentvehicles, different frequencies of application, and different methods ofapplication.

A second difficulty inherent in creating a combined formulation is thatmany anti-acne ingredients inactivate other anti-acne ingredients. Forexample, benzoyl peroxide inactivates tretinoin, erythromycin, andhydroquinone; tretinoin inactivates erythromycin; and benzoyl peroxidecan lead to oxidation of zinc pyrithione. There are likely to be manymore similar interactions that are not yet described in the dermatologyliterature.

When it is desired to use anti-photoaging ingredients in addition toanti-acne ingredients, additional interactions arise. When a patient isusing benzoyl peroxide (for acne) they should avoid using it at the sametime as hydroquinone (used for short-term treatment of photoaging), asthe combination can lead to staining of the skin. As another example,niacinamide (a vitamin B3 derivative that can be used as an anti-acneingredient and as an anti-photoaging ingredient) should not be used withascorbic acid (the naturally occurring form of vitamin C), as the formercan inactivate the latter ingredient. In addition, many photoagingtreatments cannot be used long-term because they contain steroids or ableaching agent (hydroquinone) with potential undesirable side effects.

Thus, for patients receiving treatment for both acne and photoaging,their treatments typically do not come in the same formulation, andadditionally, the patients are often instructed to use their individualformulations at different times of day, significantly decreasing theconvenience of treatment.

An additional difficulty in formulating a once-daily composition for thetreatment of acne and photoaging is that the majority of ingredients foreach of these purposes are typically applied to the skin twice daily.These ingredients that are typically applied twice daily includeclindamycin, azelaic acid, dapsone, adapalene, benzoyl peroxide,erythromycin, hydroquinone, niacinamide, ascorbic acid, magnesiumascorbyl phosphate, zinc pyrithione, and others. Even for treatment ofacne alone, once-daily treatments are not yet the norm because of thepotential inactivation of one anti-acne compound by another anti-acnecompound and using two different agents with different mechanisms ofaction often requiring different formulations.

Finally, a method to treat both acne and photoaging would require acollection of active ingredients that are stable and efficacious in thesame vehicle. In formulating a vehicle of inactive ingredients to usealong with active ingredient(s), one must account for texture, color,scent, method of application, pH, water solubility, alcohol solubility,stability of the active ingredients, and the presence or absence ofinteractions between the active ingredient(s) and the inactiveingredients. Thus for acne and photoaging to both be treated with asingle treatment is a significant advance over most currentmethodologies. A once-daily composition and method of treatment would bedesirable because a once-daily composition increases patient adherenceand lowers cost.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows Exemplary pharmaceutical compositions, Compositions B-Q.

SUMMARY

In one aspect, the current disclosure provides a composition comprisinga first anti-acne compound, a second anti-acne compound, and ananti-photoaging compound.

According to one embodiment, the composition comprises

-   -   a) a first anti-acne compound;    -   b) a second anti-acne compound, wherein each of the first and        second anti-acne compounds are selected from the group        consisting of azelaic acid, clindamycin, niacinamide, tretinoin,        and zinc pyrithione, or a pharmaceutically acceptable salt        thereof; and    -   c) an anti-photoaging compound, wherein the anti-photoaging        compound is selected from the group consisting of azelaic acid,        niacinamide, and ascorbyl phosphate, or a pharmaceutically        acceptable salt thereof,    -   wherein the first anti-acne compound, the second anti-acne        compound, and the anti-photoaging compound are three different        compounds.

In another aspect, the current disclosure provides a method for thetreatment of acne and photoaging in a subject in need thereof comprisingadministering to the skin of the subject a composition comprising

-   -   a) a first anti-acne compound;    -   b) a second anti-acne compound, wherein each of the first and        second anti-acne compounds are selected from the group        consisting of azelaic acid, clindamycin, niacinamide, tretinoin,        and zinc pyrithione, or a pharmaceutically acceptable salt        thereof; and    -   c) an anti-photoaging compound, wherein the anti-photoaging        compound is selected from the group consisting of azelaic acid,        niacinamide, and ascorbyl phosphate, or a pharmaceutically        acceptable salt thereof; and    -   d) a pharmaceutically acceptable vehicle,    -   wherein the first anti-acne compound, the second anti-acne        compound, and the anti-photoaging compound are three different        compounds.

In yet another aspect, the current disclosure provides a method for thetreatment of acne and photoaging in a subject in need thereof comprising

-   -   a) administering to the skin of the subject a first composition,        wherein the first composition comprises less than 0.025%        tretinoin and less than 12% azelaic acid;    -   b) evaluating the skin of the subject after a first interval;        and    -   c) administering a second composition comprising a higher        concentration of tretinoin or azelaic acid or both than the        first composition if the acne or photoaging requires further        improvement,    -   thereby treating acne and photoaging in the subject.

In still another aspect, the current disclosure provides a kitcomprising:

-   -   1) a composition comprising        -   a) a first anti-acne compound;        -   b) a second anti-acne compound, wherein each of the first            and second anti-acne compounds are selected from the group            consisting of azelaic acid, clindamycin, niacinamide,            tretinoin, and zinc pyrithione, or a pharmaceutically            acceptable salt thereof; and        -   c) an anti-photoaging compound, wherein the anti-photoaging            compound is selected from the group consisting of azelaic            acid, niacinamide, and ascorbyl phosphate, or a            pharmaceutically acceptable salt thereof,        -   wherein the first anti-acne compound, the second anti-acne            compound, and the anti-photoaging compound are three            different compounds;    -   2) a sealed container for housing the composition; and    -   3) instructions for use.

DETAILED DESCRIPTION

The disclosure provides a pharmaceutical composition for the treatmentof skin disorders. According to some embodiments, the pharmaceuticalcomposition is a topically administered composition. According to someembodiments, the pharmaceutical composition comprises three distinctpharmaceutical ingredients. According to some embodiments, each of thethree distinct pharmaceutical ingredients are supplied in a singletopical pharmaceutical composition. According to some embodiments, thesingle topical pharmaceutical composition is administered to the skin ofa subject in need thereof once a day.

The disclosure also provides methods of administering a pharmaceuticalcomposition with three distinct pharmaceutical ingredients supplied in asingle topical pharmaceutical composition to a subject in need thereof.According to some embodiments, the subject is suffering from a skinpathology. According to some embodiments, the skin pathology is selectedfrom acne, wrinkles, photoaging and uneven pigmentation. According tosome embodiments, administration of the topical pharmaceuticalcomposition to the skin of a subject results in reduction of fine linesand wrinkles, reduction in acne, reduction of the appearance of finelines and wrinkles, skin firming, improvement in skin texture,improvement in the skin's elasticity, improvement in skin luminosity,reduction of uneven pigmentation, skin hydration, skin moisturization,reduction in skin dehydration, and improvement of even skin tone.

According to some embodiments, the method includes evaluating the skinof a subject. According to some embodiments, the method includes theevaluation of the skin of a subject using telemedicine. According tosome embodiments, the subject is administered a first topicalpharmaceutical composition. According to some embodiments, the skin ofthe subject is reevaluated. According to some embodiments, if the skinevaluated has not improved, a second topical pharmaceutical compositionis administered. According to some embodiments, the second topicalpharmaceutical composition comprises ingredients that cause enhancedskin irritation when compared to the first topical pharmaceuticalcomposition.

The disclosure also provides kits containing the pharmaceuticalcompositions described herein for use with the methods of treatmentdescribed herein.

A. Terms, Definitions and Abbreviations

As used herein and unless otherwise expressly noted or required by thecontext, all percentages refer to percentages by weight (wt-%) of thetotal composition (w/w).

As used herein in connection with a measured quantity, for exampleweight, “about” refers to that variation in the measured quantity aswould be expected by one skilled in the art exercising a level of carecommensurate with the objective of the measurement and the equipmentused, and includes uncertainties that may be introduced by mathematicalrounding errors.

As used herein an “anti-acne” compound is a compound that treats acne,for example, reducing the amount of acne. Anti-acne compounds include,but are not limited to, comedolytics (which help keratinization and thusprevent clogged pores), antibiotics (which generally target theacne-causing bacterium Propionibacterium acnes or P. acnes), andanti-inflammatory compounds (which have a direct effect on inflammationindependent of any comedolytic or antibiotic effects). Non-limitingexamples of comedolytics include alpha hydroxy acids (e.g., glycolicacid, lactic acid, and salicylic acid), retinoids (e.g., tretinoin andisotretinoin), and saturated dicarboxylic acids (e.g., suberic acid,azelaic acid, and sebacic acid). Non-limiting examples of antibioticsinclude cephalosporins (e.g., cefoxitin, ceftazidime, and cefepime),lincosamides (e.g., clindamycin and lincomycin), macrolides (e.g.,erythromycin and azithromycin), pleuromutillins (e.g., retapamulin),metal complexes (e.g., zinc pyrithione, zinc methoxazole, and zincsulfathiazole), penicillins (e.g., amoxicillin, ampicillin, andcarbenicillin), fluoroquinolones (e.g., ciprofloxacin, clinafloxacin,ofloxacin, and trovafloxacin), retinoids (e.g., tretinoin), saturateddicarboxylic acids (e.g., suberic acid, azelaic acid, and sebacic acid),sulfonamides (e.g., sulfamethizole, sulfamethoxazole, sulfisoxazole),sulfones (e.g., dapsone or diaminodiphenyl sulfone), and tetracyclines(e.g., doxycycline and minocycline). Non-limiting examples of ananti-inflammatory compound include lincosamides (e.g., clindamycin andlincomycin), niacinamide (also known as nicotinamide andpyridine-3-corboxamide), retinoids (e.g., tretinoin), and saturateddicarboxylic acids (e.g., suberic acid, azelaic acid, and sebacic acid).For example, anti-acne compounds include azelaic acid, clindamycin,niacinamide, tretinoin, and zinc pyrithione, or a pharmaceuticallyacceptable salt thereof.

Saturated dicarboxylic acids can act as comedolytics and as antibiotics.Although azelaic acid is a preferred anti-acne compound for use in thoseembodiments of the present disclosure in which an anti-acne compound isincluded, other saturated dicarboxylic acids may also be used, includingsuberic acid and sebacic acid. Azelaic acid (also known as nonanedioicacid) is an external treatment for, for example, acne, rosacea, melasma,and postinflammatory hyperpigmentation. Azelaic acid is also used as anantifungal.

Lincosamides and macrolides are antibiotics that inhibit proteinsynthesis by binding to the 50S subunit of bacterial ribosomes and thusprevent bacteria from replicating. Although clindamycin is a preferredanti-acne compound for use in those embodiments of the presentdisclosure in which an anti-acne compound is included, otherlincosamides can also be used, including lincomycin. Clindamycin is alsoknown as(2S,4R)-N-[2-chloro-1-[(2R,3R,4R,5R,6R)-3,4,5-trihydroxy-6-methylsulfanyloxan-2-yl]propyl]-1-methyl-4-propylpyrrolidine-2-carboxamide.In some embodiments, clindamycin is used with another antibiotic. Anantibiotic combination may prevent antibiotic resistance in a subject.

Retinoids are well known to those skilled in the art of formulatingtopical dermatological compositions. Retinoids exhibit thepharmacological activity of all trans retinol and share, as a commonstructural feature, a β-ionone-type ring (2,6,6-trimethylcyclohen-1-ene)having a multiply unsaturated alkyl side chain at the 1 position of thering. Tretinoin is the carboxylic acid form of vitamin A, so tretinoin(also known as all-trans retinoic acid) is a vitamin derivative.Although tretinoin is a preferred retinoid for use in those embodimentsof the present disclosure in which a retinoid or an anti-acne compoundis included, other retinoid derivatives can also be used, includingadapalene, isotretinoin, or tazarotene.

Some metal complexes including zinc pyrithione have antibiotic effects.Although zinc pyrithione (also known as bis(2-pyridylthio)zinc1,1′-dioxide) is a preferred anti-acne compound for use in thoseembodiments of the present disclosure in which an anti-acne compound isincluded, other metal complexes can also be used, including zincmethoxazole and zinc sulfathiazole. Zinc pyrithione is also used as anantifungal. Zinc pyrithione is used to treat and prevent UV-induced skindamage and may also treat hyperpigmentation such as melasma.

The term “anti-inflammatory” compound for the purposes of the presentdisclosure refers to a compound that reduces certain signs ofinflammation and may treat inflammatory acne (e.g., papules, pustules,nodules, and cysts) independent of any comedolytic or antimicrobialeffects. For example, anti-inflammatory compounds include azelaic acid,clindamycin, niacinamide, and tretinoin.

As used herein an “anti-photoaging” compound is a compound that treatsphotoaging, for example, reducing the amount of fine wrinkles or ofhyperpigmentation. Anti-photoaging compounds include, but are notlimited to, antioxidants (e.g., vitamins or vitamin derivativesincluding, but not limited to, niacinamide and ascorbyl phosphate,ascorbyl 6 palmitate, isostearyl 2-0 L-ascorbyl phosphate, and ascorbicacid sulfate) and tyrosinase inhibitors (e.g., 4-n-butylresorcinol,azelaic acid, and kojic acid). For example, anti-photoaging compoundsinclude azelaic acid, niacinamide, and ascorbyl phosphate, or apharmaceutically acceptable salt thereof (e.g., magnesium ascorbylphosphate and sodium ascorbyl phosphate).

The term “antioxidant” for the purposes of the present disclosure refersto a chemical substance that is added to a pharmaceutical composition totreat or to prevent photoaging, for example, by inhibiting the oxidationof molecules that are present in skin or dermis of a subject. Vitaminsand vitamin derivatives are well known to those skilled in the art offormulating topical dermatological compositions. Certain vitaminderivatives have increased stability over the naturally occurring formof the vitamin. For example, some vitamin E derivatives, includingtocopheryl acetate, are more stable than the naturally occurringtocopherol (vitamin E), and some vitamin C derivatives, includingascorbyl phosphate, ascorbyl 6 palmitate, isostearyl 2-O L-ascorbylphosphate, and ascorbic acid sulfate, or pharmaceutically acceptablesalts thereof, are more stable than the naturally occurring L-ascorbicacid or ascorbate (vitamin C). Vitamin C is the most abundantantioxidant in the skin and is a cofactor in collagen production.Although magnesium ascorbyl phosphate is a preferred anti-photoagingcompound for use in those embodiments of the present disclosure in whichan anti-photoaging compound is included, other derivatives of vitamin Ccan also be used, including sodium ascorbyl phosphate and ascorbyl 6palmitate. Niacinamide is a form of vitamin B3 that fights acne viaanti-inflammatory properties and has anti-aging effects.

The term “tyrosinase inhibitor” for the purposes of the presentdisclosure refers to a chemical compound that is added to apharmaceutical composition to treat or to prevent photoaging, forexample, by reducing the production of melanin by binding to tyrosinasepresent in skin or dermis of a subject. Tyrosinase is acopper-containing oxidase that catalyzes the first two steps in theproduction of melanin. Overproduction of melanin can lead tohyperpigmentation. Although azelaic acid is a preferred anti-photoagingcompound for use in those embodiments of the present disclosure in whichan anti-photoaging compound is included, other tyrosinase inhibitor canalso be used, including 4-n-butylresorcinol and kojic acid.

An “inactive ingredient” is compatible with the other ingredients of theformulation and not injurious to the patient or to the subject.Non-limiting examples of inactive ingredients include a preservative, athickening agent, a vehicle, and a vitamin derivative.

The term “preservative” for the purposes of the present invention refersto a chemical substance that is added to a pharmaceutical composition toprevent the pharmaceutical composition from deterioration, decompositionor degradation or to substantially reduce or decelerate the degreeand/or the speed of such deterioration, decomposition or degradation.Non-limiting examples of preservatives include benzoate,ethylhexylglycerin, methyl benzoate, methyl paraben, phenoxyethanol,propionic acid, propyl paraben, and pharmaceutically acceptable saltsthereof.

The term “vehicle” refers to a substance that serves as a carrier,whether diluent or excipient, for improving the efficiency of deliveryand the effectiveness of a pharmaceutical composition. The phrase“pharmaceutically acceptable vehicle” is art recognized and includes apharmaceutically acceptable material, composition or vehicle, suitablefor administering compounds of the present invention to mammals. Thevehicles include liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting the subjectagent from one organ, or portion of the body, to another organ, orportion of the body. Each vehicle must be “acceptable” in the sense ofbeing compatible with the other ingredients of the formulation and notinjurious to the patient or to the subject. Some examples of materialswhich can serve as pharmaceutically acceptable vehicles include: water;aloe vera leaf juice; emulsifiers or thickening agents, such ascarbomer, cetearyl alcohol, cetyl alcohol, glyceryl stearate, stearicacid, xanthan gum, and viscous liquids; sugars, such as lactose, glucoseand sucrose; starches, such as corn starch and potato starch; cellulose,and its derivatives, such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin;talc; excipients, such as cocoa butter, myristyl myristate, Shea butter,and suppository waxes; oils, such as acai palm fruit oil, calendulaflower oil, corn oil, cottonseed oil, jojoba seed oil, olive oil,passion fruit seed oil, peanut oil, rice bran oil, safflower oil, sesameoil, soybean oil, and sweet almond seed oil; glycols, such as propyleneglycol; polyols, such as glycerin, vegetable glycerin, sorbitol,mannitol and polyethylene glycol (e.g., ceteareth-20 and PEG-100myristate); esters, such as ethyl oleate and ethyl laurate; agar;buffering agents, such as magnesium hydroxide and aluminum hydroxide;alginic acid; pyrogen-free water; isotonic saline; Ringer's solution;ethyl alcohol; phosphate buffer solutions; and other non-toxiccompatible substances employed in pharmaceutical formulations.

As used herein, the term “pharmaceutically acceptable salts” refers toderivatives of the disclosed compounds wherein the parent compound ismodified by converting an existing acid or base moiety to its salt form.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts of thepresent invention include the conventional non-toxic salts of the parentcompound formed, for example, from non-toxic inorganic or organic acids.The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), eachof which is incorporated herein by reference in its entirety.

B. Embodiments

In one aspect, the current disclosure provides a composition comprising

-   -   a) a first anti-acne compound;    -   b) a second anti-acne compound; and    -   c) an anti-photoaging compound,        or a pharmaceutically acceptable salt thereof.

In certain embodiments, each of the first and second anti-acne compoundsare selected from the group consisting of comedolytics and antibiotics.In some embodiments, the first and second anti-acne compounds areselected from the group consisting of cephalosporins, lincosamides,macrolides, pleuromutillins, metal complexes, penicillins,fluoroquinolones, niacinamide, retinoids, saturated dicarboxylic acids,sulfonamides, sulfones, and tetracyclines. In other embodiments, each ofthe first and second anti-acne compounds are selected from the groupconsisting of azelaic acid, clindamycin, niacinamide, tretinoin, andzinc pyrithione, or a pharmaceutically acceptable salt thereof. In someembodiments, one of the anti-acne compounds is an antibiotic. In otherembodiments, each of the first and second anti-acne compounds areantibiotics. In further embodiments, one of the anti-acne compounds isan anti-inflammatory compound. In certain embodiments, theanti-inflammatory compound is selected from the group consisting oflincosamides, niacinamide, retinoids, and saturated dicarboxylic acids.In other embodiments, the anti-inflammatory compound is selected fromthe group consisting of azelaic acid, clindamycin, niacinamide, andtretinoin, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the anti-photoaging compound is selected fromthe group consisting of an antioxidant and a tyrosinase inhibitor. Inother embodiments, the anti-photoaging compound is selected from thegroup consisting of azelaic acid, niacinamide, and ascorbyl phosphate,or a pharmaceutically acceptable salt thereof.

In one embodiment, the composition comprises clindamycin, or apharmaceutically acceptable salt thereof. In certain embodiments, thepharmaceutically acceptable salt of clindamycin is clindamycinphosphate. In other embodiments, the clindamycin, or a pharmaceuticallyacceptable salt thereof, can range, e.g., from about 0.1 to about 10%,and more usually 0.4 to 2% (e.g., 0.5 to 1.5%) of the composition w/w.For example, clindamycin phosphate may make up between 0.5 and 1.5% ofthe composition w/w.

In another embodiment, the composition comprises niacinamide, or apharmaceutically acceptable salt thereof. In some embodiments, theniacinamide, or a pharmaceutically acceptable salt thereof, can range,e.g., from about 0.1 to about 15%, and more usually 2 to 8% (e.g., 2 to6%) of the composition w/w.

In yet another embodiment, the composition comprises tretinoin, or apharmaceutically acceptable salt thereof. In some embodiments, thetretinoin, or a pharmaceutically acceptable salt thereof, can range,e.g., from about 0.001 to about 1%, and more usually 0.005 to 0.3%(between, e.g., 0.005 and 0.2%, 0.009 and 0.15%, 0.017 and 0.1%, 0.01 to0.1%, and 0.02 and 0.14%) of the composition w/w.

In other embodiments, the composition comprises zinc pyrithione, or apharmaceutically acceptable salt thereof. In some embodiments, the zincpyrithione, or a pharmaceutically acceptable salt thereof, can range,e.g., from about 0.01 to about 2%, and more usually 0.05 to 1% (e.g.,0.1 to 0.5%) of the composition w/w.

In still another embodiment, the composition comprises azelaic acid, ora pharmaceutically acceptable salt thereof. In some embodiments, theazelaic acid, or a pharmaceutically acceptable salt thereof, can range,e.g., from about 0.1 to about 25%, and more usually 3 to 20% (e.g., 4 to20%) of the composition w/w.

In a further embodiment, the composition comprises a vitamin Cderivative, or a pharmaceutically acceptable salt thereof. In certainembodiments, the pharmaceutically acceptable salt of a vitamin Cderivative is magnesium ascorbyl phosphate. In some embodiments, thevitamin C derivative, or a pharmaceutically acceptable salt thereof, canrange, e.g., from about 0.1 to about 25%, and more usually 1 to 15%(e.g., 3 to 10% and 2 to 8%) of the composition w/w.

In some embodiments, the first and second anti-acne compounds aredifferent anti-acne compounds. In some embodiments the first and secondanti-acne compounds are selected from the group consisting of azelaicacid and clindamycin; azelaic acid and niacinamide; azelaic acid andtretinoin; azelaic acid and zinc pyrithione; clindamycin andniacinamide; clindamycin and tretinoin; clindamycin and zinc pyrithione;niacinamide and tretinoin; niacinamide and zinc pyrithione; andtretinoin and zinc pyrithione, or pharmaceutically acceptable saltsthereof.

In some embodiments, the first and second anti-acne compounds aredifferent from the anti-photoaging compound. In other embodiments, afirst anti-acne compound, a second anti-acne compound, and ananti-photoaging compound are three different compounds. In still otherembodiments, if first or second anti-acne compound is azelaic acid, thenthe anti-photoaging compound is not azelaic acid. In furtherembodiments, if first or second anti-acne compound is niacinamide, thenthe anti-photoaging compound is not niacinamide. In another embodiment,if the anti-photoaging compound is azelaic acid, then neither the firstnor the second anti-acne compounds are azelaic acid. In yet anotherembodiment, if the anti-photoaging compound is niacinamide, then neitherthe first nor the second anti-acne compounds are niacinamide.

In certain embodiments, the composition comprising a first anti-acnecompound, a second anti-acne compound, and an anti-photoaging compoundis selected from the group consisting of azelaic acid, clindamycin, anda vitamin C derivative; azelaic acid, clindamycin, and ascorbylphosphate; azelaic acid, niacinamide, and a vitamin C derivative;azelaic acid, niacinamide, and ascorbyl phosphate; azelaic acid,tretinoin, and niacinamide; azelaic acid, tretinoin, and a vitamin Cderivative; azelaic acid, tretinoin, and ascorbyl phosphate; azelaicacid, zinc pyrithione, and a vitamin C derivative; azelaic acid, zincpyrithione, and ascorbyl phosphate; clindamycin, niacinamide, andazelaic acid; clindamycin, niacinamide, and a vitamin C derivative;clindamycin, niacinamide, and ascorbyl phosphate; clindamycin,tretinoin, and azelaic acid; clindamycin, tretinoin, and niacinamide;clindamycin, tretinoin, and a vitamin C derivative; clindamycin,tretinoin, and ascorbyl phosphate; clindamycin, zinc pyrithione, andazelaic acid; clindamycin, zinc pyrithione, and niacinamide;clindamycin, zinc pyrithione, and a vitamin C derivative; clindamycin,zinc pyrithione, and ascorbyl phosphate; niacinamide, tretinoin, andazelaic acid; niacinamide, tretinoin, and a vitamin C derivative;niacinamide, tretinoin, and ascorbyl phosphate; niacinamide, zincpyrithione, and azelaic acid; niacinamide, zinc pyrithione, and avitamin C derivative; niacinamide, zinc pyrithione, and ascorbylphosphate; tretinoin, zinc pyrithione, and azelaic acid; tretinoin, zincpyrithione, and niacinamide; tretinoin, zinc pyrithione, and a vitamin Cderivative; and tretinoin, zinc pyrithione, and ascorbyl phosphate, orpharmaceutically acceptable salts thereof. In some embodiments, thecomposition comprises tretinoin, ascorbyl phosphate, and azelaic acid.

In certain embodiments, the anti-photoaging compound is selected fromthe group consisting of an antioxidant and a tyrosinase inhibitor. Insome embodiments, the anti-photoaging compound is not a steroid or ableaching agent (e.g., hydroquinone). In other embodiments, theanti-photoaging compound is selected from the group consisting ofazelaic acid, niacinamide, and ascorbyl phosphate, or a pharmaceuticallyacceptable salt thereof.

In some embodiments the composition comprises a first and a secondanti-acne compounds selected from the group consisting of 0.5 to 1.5%clindamycin, 2 to 6% niacinamide, 0.005 to 0.3% tretinoin, and 0.1 to0.5% zinc pyrithione, or a pharmaceutically acceptable salt thereof; andan anti-photoaging compound selected from the group consisting of 4 to20% azelaic acid; 2 to 6% niacinamide, and 3 to 10% a vitamin Cderivative, or a pharmaceutically acceptable salt thereof. In someembodiments, the composition comprises 2 to 6% niacinamide, 0.005 to0.3% tretinoin, and 3 to 10% of a vitamin C derivative of thecomposition w/w. For example, the composition may comprise about 4%niacinamide, 0.005 to 0.3% tretinoin, and about 5% of a vitamin Cderivative; about 4% niacinamide, 0.005 to 0.3% tretinoin, and about 5%magnesium ascorbyl phosphate, of the composition w/w.

In certain embodiments, the composition further comprises apharmaceutically acceptable vehicle. In some embodiments, thecomposition further comprises one or more inactive ingredients. In otherembodiments, at least one inactive ingredient is a pharmaceuticallyacceptable vehicle. In still other embodiments, at least one inactiveingredient is a preservative. In some embodiments, the compositionfurther comprises at least one pharmaceutically acceptable vehicle, atleast one emulsifier, at least one excipient, at least one oil, at leastone polyol, and at least one preservative. In certain embodiments, thecomposition further comprises one or more of the following inactiveingredients water, vegetable glycerin, stearic acid, myristyl myristate,cetearyl alcohol, ceteareth-20, glyceryl stearate, jojoba seed oil,soybean oil, cetyl alcohol, carbomer, shea butter, calendula flower oil,passion fruit seed oil, rice bran oil, acai palm fruit oil,phenoxyethanol, ethylhexylglycerin. In one embodiment, the compositionfurther comprises the following inactive ingredients water, glycerin,aloe vera leaf juice, PEG-100 myristate, sweet almond seed oil, xanthangum, methyl paraben, propyl paraben, and tocopheryl acetate.

In certain embodiments, a first anti-acne compound, a second anti-acnecompound, and an anti-photoaging compound are administeredsimultaneously. In some embodiments, a first anti-acne compound, asecond anti-acne compound, and an anti-photoaging compound are active atthe same pH or in the same pH range. In other embodiments, the pH of thecomposition can range, e.g., from about 3.0 to about 7.0, and moreusually from about 3.5 to about 6.0 (e.g., from 4.0 to 5.0).

In some embodiments, the composition batch size can range, e.g., fromabout 5 g to about 100 kg, and more usually 100 g to 10 kg (e.g., 0.5 kgto 3 kg). In certain embodiments, the composition batch is divided into30 g aliquots. In some embodiments, the composition batch size canrange, e.g., from about 5 mL to about 100 L, and more usually 100 mL to10 L (e.g., 0.5 L to 3 L). In certain embodiments, the composition batchis divided into 30 mL aliquots.

In another aspect, the current disclosure provides a compositioncomprising a first antibiotic, a second antibiotic and a vitamin or avitamin derivative, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the first and second antibiotics are distinctantibiotics. In some embodiments, each of the first and secondantibiotics are selected from the group consisting of lincosamides,metal complexes, and saturated dicarboxylic acids. In certainembodiments, each of the first and second antibiotics are selected fromthe group consisting of azelaic acid, clindamycin, and zinc pyrithione.In still other embodiments, the vitamin or a vitamin derivative, or apharmaceutically acceptable salt thereof, are selected from the groupconsisting of tretinoin, niacinamide, a vitamin C derivative (e.g.,ascorbyl phosphate).

In certain embodiments, the composition comprising a first antibiotic, asecond antibiotic and a vitamin or a vitamin derivative, or apharmaceutically acceptable salt thereof, is selected from the groupconsisting of azelaic acid, clindamycin, and tretinoin; azelaic acid,clindamycin, and niacinamide; azelaic acid, clindamycin, and a vitamin Cderivative; azelaic acid, zinc pyrithione, and tretinoin; azelaic acid,zinc pyrithione, and niacinamide; azelaic acid, zinc pyrithione, and avitamin C derivative; clindamycin, zinc pyrithione, and tretinoin;clindamycin, zinc pyrithione, and niacinamide; and clindamycin, zincpyrithione, and a vitamin C derivative, or pharmaceutically acceptablesalts thereof.

In a further aspect, the current disclosure provides a compositioncomprising a first anti-inflammatory, a second anti-inflammatory, and anantifungal or an antioxidant, or a pharmaceutically acceptable saltthereof.

In some embodiments, each of the first and second anti-inflammatorycompounds are selected from the group consisting of lincosamides,niacinamide, retinoids, and saturated dicarboxylic acids. In otherembodiments, each of the first and second anti-inflammatory compoundsare selected from the group consisting of azelaic acid, clindamycin,niacinamide, and tretinoin, or a pharmaceutically acceptable saltthereof.

In other embodiments, the antifungal is selected from the groupconsisting of azelaic acid, ketoconazole, and zinc pyrithione, or apharmaceutically acceptable salt thereof. In still other embodiments,the antioxidant is selected from the group consisting of niacinamide anda vitamin or a vitamin derivative, or a pharmaceutically acceptable saltthereof. In certain embodiments, the antioxidant is selected from thegroup consisting of niacinamide and a vitamin C derivative (e.g.,ascorbyl phosphate).

In other embodiments, the composition is administered topically. Thetopical compositions of the present disclosure can be provided in theform of a cream (ointment), a gel, or lotion. Creams are particularlypreferred. The pharmaceutically acceptable vehicle is selected accordingto the desired final form of the topical composition (cream or ointment,gel, lotion, and the like) from the types of vehicles known in the artfor topical application of active ingredients.

In some embodiments, the frequency of application of the disclosedcompositions to the skin of a subject may be one, two, or three timesper day. In certain embodiments, the frequency of application is onceper day.

In another aspect, the current disclosure provides a method for thetreatment of acne and photoaging in a subject in need thereof comprisingadministering to the skin of the subject a composition comprising

-   -   a) a first anti-acne compound;    -   b) a second anti-acne compound, wherein each of the first and        second anti-acne compounds are selected from the group        consisting of azelaic acid, clindamycin, niacinamide, tretinoin,        and zinc pyrithione, or a pharmaceutically acceptable salt        thereof;    -   c) an anti-photoaging compound, wherein the anti-photoaging        compound is selected from the group consisting of azelaic acid,        niacinamide, and ascorbyl phosphate, or a pharmaceutically        acceptable salt thereof; and    -   d) a pharmaceutically acceptable vehicle,    -   wherein the first anti-acne compound, the second anti-acne        compound, and the anti-photoaging compound are three different        compounds.

In yet another aspect, the current disclosure provides a method for thetreatment of acne and photoaging in a subject in need thereof comprising

-   -   a) administering to the skin of the subject a first composition,        wherein the first composition comprises less than 0.025%        tretinoin and less than 12% azelaic acid;    -   b) evaluating the skin of the subject after a first interval;        and    -   c) administering a second composition comprising a higher        concentration of tretinoin or azelaic acid or both than the        first composition if the acne or photoaging requires further        improvement,        thereby treating acne and photoaging in the subject.

In some embodiments, a first composition is administered to the skin ofa subject. In some embodiments, the first composition is selected fromthe group consisting of clindamycin, niacinamide, and azelaic acid;clindamycin, niacinamide, and a vitamin C derivative; clindamycin,niacinamide, and ascorbyl phosphate; clindamycin, tretinoin, and azelaicacid; clindamycin, tretinoin, and niacinamide; clindamycin, tretinoin,and a vitamin C derivative; clindamycin, tretinoin, and ascorbylphosphate; clindamycin, zinc pyrithione, and azelaic acid; clindamycin,zinc pyrithione, and niacinamide; clindamycin, zinc pyrithione, and avitamin C derivative; clindamycin, zinc pyrithione, and ascorbylphosphate; niacinamide, tretinoin, and azelaic acid; niacinamide,tretinoin, and a vitamin C derivative; niacinamide, tretinoin, andascorbyl phosphate; niacinamide, zinc pyrithione, and azelaic acid;niacinamide, zinc pyrithione, and a vitamin C derivative; niacinamide,zinc pyrithione, and ascorbyl phosphate; tretinoin, zinc pyrithione, andazelaic acid; tretinoin, zinc pyrithione, and niacinamide; tretinoin,zinc pyrithione, and a vitamin C derivative; and tretinoin, zincpyrithione, and ascorbyl phosphate, or pharmaceutically acceptable saltsthereof.

In other embodiments, the first composition is a less irritatingformulation, for example, the first composition comprises little or notretinoin and azelaic acid. In further embodiments, the firstcomposition does not include tretinoin or azelaic acid. In certainembodiments, the first composition comprises less than 0.025% tretinoinand less than 12% azelaic acid. In some embodiments, the firstcomposition comprises clindamycin, zinc pyrithione, and niacinamide. Incertain embodiments, the first composition comprises clindamycin,azelaic acid, and niacinamide.

In some embodiments, evaluating the skin of the subject includesevaluating skin brightness, discoloration, fine lines, and wrinkles. Incertain embodiments, evaluating the skin of the subject includes one ormore of the following: creation and use of a portal (e.g., through theinternet), which allows secure examination of high-resolutionphotographs; remote examination of high-resolution photographs; and inperson examination by a qualified grader. In other embodiments,evaluating the skin of the subject is a form of telemedicine via secureuploading of the subject's medical history and digital high-resolutionphotographs online or through the internet. In still other embodiments,evaluating the skin of the subject includes evaluating skin byprofilometry; evaluating skin tone; evaluating skin color; evaluatingskin firmness; evaluating skin elasticity; evaluating skin hydration;and evaluating skin aging by visual assessments. In some embodiments,evaluating the skin of the subject includes one or more of thefollowing: profilometric analysis; measurements with a CUTOMETER® MPA580; measurements with a CHROMAMETER CR200®, measurements with aCORNEOMETER® CM825; expert visual assessments; and visual assessmentswith Visia CR Capture.

In some embodiments, effects including, but non-limited to,anti-wrinkle, visible reduction of fine lines and wrinkles, reduction ofthe appearance of fine lines and wrinkles, skin firming, improvement inskin texture, improvement in the skin's elasticity, improvement in skinluminosity, reduction of uneven pigmentation, hydrating, moisturizing,combating skin dehydration, and encouraging even skin tone are evaluatedafter an interval of time. In other embodiments, improvement of acne,e.g., less acne, or of photoaging, e.g., less discoloration, fine lines,and/or wrinkles, is evaluated after an interval of time. The interval oftime can range, e.g., from about 1 day to about a year, and more usually1 week to 6 months (e.g., 4, 8, and 12 weeks). In some embodiments, thefirst interval is four weeks. In other embodiments, evaluating the skinof the subject occurs at one or more intervals of time over the courseof treatment. In some embodiments, the method of treatment of acne andphotoaging in a subject in need thereof is applied over a period of timethat can range, e.g., from about 1 day to about 50 years, and moreusually 1 week to about 25 years (e.g., 3 months, 6 months, 1 year, 5years, and 10 years).

In other embodiments, the acne is caused by P. acnes. In otherembodiments, the antimicrobial may target one or more of the followingbacteria P. acnes, Staphylococcus aureus, and Staphylococcus epidermis.

In some embodiments, the acne is non-inflammatory acne, also known ascomedones, (e.g., blackheads and white heads). In other embodiments, theacne is inflammatory acne (e.g., papules, pustules, nodules, and cysts).In still other embodiments, the acne is a combination ofnon-inflammatory acne and inflammatory acne.

In certain embodiments, the acne may be classified by its severity. Whena subject has several comedones but very few papules and pustules, thenthe subject has mild acne. If a subject has a mix of comedones andseveral inflamed papules and pustules existing together, the acne ismild to moderate acne. If a subject has also has some nodules along withpapules and pustules, the acne is moderate acne. Deep cysts or any typeof acne that leaves behind permanent pitted or saucer-shaped scars iscategorized as severe acne. In certain embodiments, evaluating the skinof the subject includes evaluating the severity of the acne.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved

In some embodiments, a second composition is administered to the skin ofa subject upon evaluation of the skin of the subject after a firstinterval of time. In certain embodiments, the acne or photoaging has notimproved, so a second composition comprising a higher concentration oftretinoin or azelaic acid compared to the first composition isadministered to the skin of a subject. In some embodiments, the secondcomposition comprises a higher concentration of tretinoin thanpreviously administered to the subject in the first composition. Forexample, the concentration of tretinoin may increase from 0% to 0.009,0.012, 0.017, 0.018, 0.02, 0.035, 0.04, 0.05, 0.06, 0.07, 0.09, 0.1,0.14, or 0.15% of the composition w/w. In certain embodiments, thesecond composition comprises clindamycin, niacinamide, and azelaic acid.In other embodiments, the second composition comprises clindamycin,tretinoin, and azelaic acid. In further embodiments, the secondcomposition comprises tretinoin, zinc pyrithione, and azelaic acid. Inanother embodiment, the second composition comprises tretinoin, azelaicacid, and a vitamin C derivative.

In other embodiments, a third composition is administered to the skin ofa subject upon evaluation of the skin of the subject after a secondinterval of time. In certain embodiments, the acne or photoaging has notimproved, so a third composition that fine tunes the treatment of acneor improves the treatment of photoaging is administered to the skin of asubject. In other embodiments, the third composition comprisesclindamycin, tretinoin, and azelaic acid. In further embodiments, thethird composition comprises tretinoin, zinc pyrithione, and azelaicacid. In another embodiment, the third composition comprises tretinoin,azelaic acid, and a vitamin C derivative.

In certain embodiments, more than two compositions are administered tothe skin of the subject in a method for the treatment of acne andphotoaging in a subject in need thereof. The skin of the subject isevaluated after an interval of time, and a different composition isadministered to the subject. Each composition administered to thesubject after the first composition or after the second compositioncomprises tretinoin. In some embodiments, the composition comprises ahigher concentration of tretinoin than previously administered to thesubject. For example, the concentration of tretinoin may increase from0% to 0.009, 0.012, 0.017, 0.018, 0.02, 0.035, 0.04, 0.05, 0.06, 0.07,0.09, 0.1, 0.14, or 0.15% of the composition w/w. However, the increasein the concentration of tretinoin may not be strictly sequential, thatis, any composition comprising a higher concentration of tretinoin thanthe concentration of tretinoin previously administered to the subjectmay be used (e.g., 0.09% to 0.018%; 0.012% to 0.035%; 0.017% to 0.35%;0.04% to 0.1%; 0.05% to 0.1%; and 0.06% to 0.14% of the compositionw/w).

It will be understood by those having ordinary skill in the art that thespecific dose level and frequency of dosage for any particular patientor subject may be varied and will depend upon a variety of factorsincluding the activity of the specific composition employed, themetabolic stability and length of action of that composition, the age,body weight, general health, gender, diet, and the severity of theparticular dermatological condition being treated. In addition specificdose level and frequency of dosage for any particular patient also maydepend on factors including, but not limited to, skin sensitivity, othermedications, acne type, allergies, and prior experiences withdermatologic treatments. For example, some patients may be treated usingmethods of this disclosure over a period of years if the acne orphotoaging is a chronic condition.

In additional embodiments, pharmaceutical kits are provided. The kitincludes a sealed container approved for the storage of pharmaceuticalcompositions, the container containing one of the above-describedpharmaceutical compositions. In some embodiments, the sealed containerminimizes the contact of air with the ingredients, e.g. an airlessbottle. In other embodiments, the sealed container is a sealed tube. Incertain embodiments, the sealed container is not a pump bottle. Aninstruction for the use of the composition and the information about thecomposition are to be included in the kit.

The following examples are provided to further elucidate the advantagesand features of the present application, but are not intended to limitthe scope of the application. The examples are for the illustrativepurposes only. USP pharmaceutical grade products were used in preparingthe formulations described below.

EXAMPLE 1. PREPARING A PHARMACEUTICAL COMPOSITION

Pharmaceutical compositions were prepared as described below. Thefollowing products were used in the amounts and concentrationsspecified, sufficient to prepare 500 g. A composition comprising a firstanti-acne compound, a second anti-acne compound, and an anti-photoagingcompound was prepared according to the following formulation:

TABLE 1 Exemplary Composition A Ingredient % of the Composition w/wTretinoin 0.02 Niacinamide 4 Magnesium ascorbyl phosphate 5 WaterGlycerin Aloe vera leaf juice PEG-100 myristate Sweet almond seed oilMethyl paraben Propyl paraben Tocopheryl acetate

In FIG. 1 and Table 3, the abbreviations used are as follows: azelaicacid (AzA); clindamycin (Clinda); niacinamide (Nia); tretinoin (Tret);magnesium ascorbyl phosphate (VitC); and zinc pyrithione (Zinc). In FIG.1 , the percentage values correspond to the amount of tretinoin by % ofthe composition w/w. The shading of FIG. 1 corresponds to the potentialof the composition to cause irritation to the skin of the subject withdarker grays corresponds to higher potential to cause irritation.

Compositions comprising a first anti-acne compound, a second anti-acnecompound, and an anti-photoaging compound were prepared according to thefollowing formulations:

TABLE 3 Exemplary pharmaceutical compositions, Compositions R-W.Formulation Formulation Active Ingredients Composition R 1% Clinda, 4%AzA, 0.25% Zinc Composition S 1% Clinda, 4% Nia, 0.25% Zinc CompositionT 1% Clinda, 4% Nia, 4% AzA Composition U 1% Clinda, 4% Nia, 0.25% ZincComposition V 1% Clinda, 4% Nia, 4% AzA Composition W 0.02% Tretinoin,4% Niacinamide

The compositions also may comprise the components listed in FIG. 1 or inTable 3 above and further comprise at least one pharmaceuticallyacceptable vehicle, at least one emulsifier, at least one excipient, atleast one oil, at least one polyol, and at least one preservative.

EXAMPLE 2. STABILITY DATA FOR PHARMACEUTICAL COMPOSITIONS

The compositions prepared according to the formulations as described inExample 1, Table 3 were then analyzed for the stability of thecompositions over time.

TABLE 4 Percent change in total active ingredients measured andcalculated for various example compositions of the invention. ActiveIngredient Stability Ratio at Room Temp. Formulation Description T0 1month 3 months 1% Clindamycin 0.00 0.952 0.868 1% Clinda, 2%Ketoconazole 0.00 0.981 0.952 1% Clinda, 4% AzA, 0.25% Zinc 0.00 1.0281% Clinda, 4% Nia, 0.25% Zinc 0.00 0.931 1% Clinda, 4% Nia, 0.25% AzA0.00 0.902 4% Niacinamide 0.00 0.9908 0.02% Tretinoin, 4% Niacinamide0.00 0.991 1% Clinda, 4% Nia, 0.25% Zinc 0.00 1.078 1% Clinda, 4% Nia,0.25% AzA 0.00 1.045 0.02% Tretinoin 0.00 1.048 0.02% Tretinoin, 4%Niacinamide 0.00 0.903 0.06% Tretinoin, 4% Nia, 5% VitC 0.00 0.981 0.948

In the above table, the abbreviations used are as follows: azelaic acid(AzA); clindamycin (Clinda); niacinamide (Nia); magnesium ascorbylphosphate (VitC); and zinc pyrithione (Zinc). Table 4 shows the percentchange in total active ingredients measured and calculated for examplecompositions of the invention. To obtain the data in Table 4, eachcomposition was maintained at room temperature for various time periods(about 1 and about 3 months) before measuring the stability of theactive ingredients according to the following method.

The stability of the active ingredients was calculated based on HPLCdata using the following equation:

$\frac{\left( {{Measured}\%{of}{Active}{ingredient}{after}a{time}{period}} \right)}{\left( {{Initial}{Measured}\%{of}{Active}{ingredient}} \right.}$

The compositions remained stable over a time interval of about 100 days.The active ingredients were not degraded or deactivated.

EXAMPLE 3. EVALUATING THE SKIN BY PROFILOMETRY

The skin of the subject was evaluated based on profilometry. Subjectswere positioned on their backs with their head in line with the midlineof their body. They were asked to close their eyes and maintain aneutral expression. Test sites on the skin of the subject were locatedusing replica locating rings ensuring that each ring lay flat on theskin. The skin was not stretched or pulled during ring placement. Eachring was placed on the left and right periorbital areas of the face withthe tab directed towards the back of the head. The foam and paperportions of each ring were aligned. Subjects were asked to turn theirhead so that the side of the head being evaluated was as horizontal aspossible. The transparency film was then placed over the subject's face.Full locating rings, with centers, were then placed onto the filmexactly over the site which had been selected. Landmarks were thentraced onto the film using an indelible marker pen. The film was thenremoved from the face and labelled to identify the subject. The film wasstored in a cool, dry location until next use.

Replica Generation

The subject was placed in an identical manner to that described aboveand landmarks on the transparency film were lined up with the subject'sfacial features. A skin marker pen was then used to make dots throughthe film onto the face of the subject to enable exact location of thetest sites. The ring was then positioned on the face, and the replicasgenerated by filling the well in the center of the ring with SILFLO® (JSDavis, Hert) material. Once the replica had set completely(approximately 5 minutes), it was removed from the skin, allowed to dryskin side up for a few minutes, and then placed in a storage sleeve.

Profilometric Analysis

The following equipment and software was used:

PC: IBM compatible Pentium III 500 MHz with 256 MB memory running underWindows 2000 Professional. Video: Cohu solid state B&W camera, 50 mmlens/30 mm extension, Coreco TCI; Ultra frame grabber. OPTIMAS v6.5,Microsoft EXCEL 2000, StatSoft STATISTICA 6. A collimated light sourcedirected at a 25° angle from the plane of the replica was used.

The replica was placed in a holder that fixed the direction of the tabposition of the replica so that the replica could be rotated to alignthe tab direction normal or parallel to the incident light direction.The replicas were taken from the crow's feet area adjacent to each eyewith the tab direction pointing toward the ear. The NORMAL samplingorientation provides texture measurements sensitive to the MAJOR,expression-induced lines (crow's feet). The PARALLEL samplingorientation provides texture measurements sensitive to the MINOR, finelines. The general background gradient of light intensity was adjustedby applying a 1st order correction in the direction of the lightpropagation. The shadow texture produced by the oblique lighting of thenegative replica was analysed by two types of assay methods:

Method A

Measuring the luminance along a set of 10 equal length parallel lines(passes) running across the replica parallel to the lighting direction.The variations in luminance were treated as indicative of the roughnessand analyzed by traditional surface roughness statistics:

Rz—the average maximum difference in luminance value for five equallength segments in each of the 10 lines traversing the sample.

Ra—the average deviation of the luminance curve about the mean luminancefor the same 10 lines.

The “R” parameters are reported in the units of brightness (Grey Levels)ranging from 0 to 255.

FSpace—distance between markers placed on the lines at luminance changesindicative of fine lines.

FNum—number markers per mm placed on the lines at luminance changesindicative of fine lines.

Method B

The replica image area was then divided into 10 equal width bands orsub-areas. The shadow-like features were detected in each of these bandsaccording to their luminance values being less than the detectionthreshold. Four parameters were determined from the detected features.

Spacing—the mean distance in millimetres between adjacent detectedfeatures (i.e., spacing between the midpoints of adjacent shadowyfeatures).

Breadth—the average breadth in millimetres of the detected features inmillimetres. This parameter is proportional to the depth of the wrinkleproducing the shadow.

Shadows—percent of the sampled replica area with luminance values lessthan the detection threshold. This is the relative area of shadows castby the wrinkles and fine lines in the replica.

NumWr—the total number of features detected in the 10 bands or sub-areasused to calculate spacing and breadth.

EXAMPLE 4. EVALUATING THE SKIN FIRMNESS AND ELASTICITY

The skin of the subject was evaluated based on measurements to study anychanges in the viscoelastic properties of the skin by the compositionsof the disclosure were performed using the CUTOMETER® MPA 580 (Courageand Khazaka, Germany). The measuring principle is based on the suctionmethod. Negative pressure is created in the device, and the skin isdrawn into the aperture of the probe. Inside the probe, the penetrationdepth is determined by a noncontact optical measuring system. Thisoptical measuring system consists of a light source and a lightreceptor, as well as two prisms facing each other, which project thelight from transmitter to receptor. The light intensity varies due tothe penetration depth of the skin. The resistance of the skin to besucked up by the negative pressure (firmness) and its ability to returninto its original position (elasticity) are displayed as curves at theend of each measurement using MICROSOFT WINDOWS® based software.

EXAMPLE 5. EVALUATING THE SKIN TONE AND COLOR

The skin of the subject was evaluated based on instrumental measurementsof skin tone and color were performed using a CHROMAMETER CR300®(Courage and Khazaka, Germany) in person. The measuring head of theCR-300 uses diffuse illumination/0° viewing geometry. A pulsed xenon arc(PXA) lamp inside a mixing chamber provides diffuse, uniform lightingover the 8 mm-diameter specimen area. Only the light reflectedperpendicular to the specimen surface is collected by the optical-fibercable for color analysis. This instrument measures the amount of lightreflected from the skin and quantifies this into a numerical value usingthe L*a*b* color scale, where L*(100) equates to total white and L*(0)equates to total black. Therefore, the L* value is inverselyproportional to the Fitzpatrick visual scale of skin tone. Theinstrument was allowed to warm up for 30 minutes prior to use.

EXAMPLE 6. EVALUATING THE SKIN HYDRATION

The skin of the subject was evaluated based on moisturizationmeasurements to study the humectant properties of the compositions ofthe disclosure were performed using the CORNEOMETER® CM825 (Courage andKhazaka, Germany). This instrument relies on the dielectric constant, aphysical property of water, which is relatively high and as such willaffect the capacitance of a capacitor. Any change in the dielectricconstant due to skin moisture variations will alter the capacitance ofthe precision capacitor in the instrument. These variations are detectedelectronically and are converted into a value by the CORNEOMETER®. A 15minute warm-up period was allowed before using the CORNEOMETER®.

Three measurements were made using the probe attachment of theCORNEOMETER® at each of the test sites on the skin of the subject,between each assessment the probe attachment of the Corneometer® waspressed onto a dry tissue. The next assessment was not performed until avalue of 5 or less was displayed by the instrument. Subjects must havebeen in the controlled environment (at a temperature of 22° C.±2° C. andat a relative humidity of 45%±5%) for at least 30 minutes prior to anyassessments being performed.

EXAMPLE 7. EVALUATING THE SKIN BY EXPERT VISUAL ASSESSMENT

The skin of the subject was evaluated by the same qualified grader ateach time-point for the duration of the study according to the GlogauClassification of Aging scale (see Table 5). Illumination of the testsites on the skin of the subject was by a 60 watt pearl bulb placedapproximately 30 cm from the test site on the skin of the subject.

TABLE 5 The Glogau Classification of Aging scale Classi- TypicalDescrip- Group fication Age tion Skin Characteristics I Mild 28-35 NoEarly Photoaging: mild wrinkles pigment changes, no keratosis, minimalwrinkles, minimal or no makeup II Moderate 35-50 Wrinkles Early toModerate Photoag- in motion ing: Early brown spots visible, keratosispalpable but not visible, parallel smile lines begin to appear, wearssome foundation III Advanced 50-65 Wrinkles Advanced Photoaging: Obvi-at rest ous discolorations, visible capillaries (telangiectasias),visible keratosis, wears heavier foundation always IV Severe 60-75 OnlySevere Photoaging: Yellow- wrinkles gray skin color, prior skinmalignancies, wrinkles throughout - no normal skin, cannot wear makeupbecause it cakes and cracks

EXAMPLE 8. EVALUATING THE SKIN BY VISUAL ASSESSMENT WITH VISIA CRCAPTURE

The skin of the subject was photographed and could be evaluated by thesame qualified grader at each time-point for the duration of the studyaccording to the Glogau Classification of Aging scale (see Table 5). TheVisia-CR captures multiple lighting modalities in onecomputer-controlled sequence. Subjects can be photographed usingstandard light, UV, cross-polarization and parallel polarizationtechniques. The Visia-CR was used to capture one full-face, and twoside-view images (one left side and one right side), high-resolutiondigital image of each subject with their eyes closed. Subjects wereinstructed to remain in a relaxed state while photos were captured usingthe Visia-CR equipment.

EXAMPLE 9. CLINICAL STUDY WITH A COMPOSITION

The composition prepared as described in Example 1, Table 1 was thenevaluated for effects for treatment of acne and photoaging. A testcomposition comprised 0.02% tretinoin, 4% niacinamide, and 5% magnesiumascorbyl phosphate of the composition w/w. The test composition wasevaluated in a single-blind, bi-lateral facial site, study in subjectsaged at least 35 years with aged skin compared to an untreated site.There were 29 subjects recruited into the study, and 23 healthysubjects, who completed the study. Usage was evaluated over a timeinterval of 12 weeks. Aged skin included moderate hyperpigmentation orphotoaging in the face, hands, or décolletage areas (minimum of Grade IIon Glogau classification scale, see Table 5).

Exclusion criteria included one or more of the following pregnancy orlactation; inadequate or non-existent contraception (women of childbearing potential only); a current skin disease of any type apart frommild facial acne (e.g. eczema, psoriasis); heavy alcohol consumption(i.e. more than 14 units per week or 4 units a day); current use orhistory of repeated use of street drugs; a febrile illness lasting morethan 24 hours in the six days prior to study commencement; significantpast medical history of hepatic, renal, cardiac, pulmonary, digestive,haematological, neurological, locomotor or psychiatric disease; historyof asthma only if requiring regular medication or hay fever thatrequired prescription treatment in two or more of the previous threeyears; a history of multiple drug hypersensitivity; concurrentmedication likely to affect the response to the test articles or confusethe results of the study; known sensitivity to the test articles ortheir constituents including packaging materials; current treatment by aphysician for allergy unless physician consulted and participationapproved; participation in a skin lightening or anti-ageing study in themonth prior to study state date; recent immunization (less than 10 daysprior to test commencement); a medical history indicating atopy(tendency to develop allergic diseases including eczema); nomicrodermabrasion treatment or superficial/light chemical peel on anystudy site within 30 days prior to the study period; and no use ofprescription skin creams containing tretinoin or use of non-prescriptionretinol containing skin creams.

Prohibitions and restrictions for the duration of the study included nouse of sun beds or sun lamps for the duration of the study; noimmunization from ten days prior to first assessment and product usageuntil completion of the study; no use of anti-ageing products/treatmentsfor the duration of the study in the assessed areas other than thoseissued/allocated; and discontinue use of any products containinghydroquinone, glycolic acid, alpha-hydroxy acids, salicylic acid,retinol, peptides and ascorbic acid (vitamin C including derivatives)for the study duration.

TABLE 6 Some demographic information on the subjects Age Range No. ofFemales No. of Males 36-40 5 0 41-45 5 0 46-50 3 0 51-55 4 0 56-60 0 261+ 7 1

Profilometery assessments were performed according to the methodsdescribed in Example 3. Profilometery assessments of the visibleappearance of fine lines and wrinkles show a highly statisticallysignificant improvement at all time-points of the study with a reductionin the appearance of fine lines and wrinkles of 4.35% (week 4), 6.47%(week 8) and 8.55% (week 12) (Table 7). The untreated control siteshowed no statistically significant reduction in the appearance of finelines and wrinkles at any timepoint of the study compared to baselinemeasurements (Table 8).

TABLE 7 Profilometery data for treated areas of the skin of the subjectsTreated Baseline Week 4 Week 8 Week 12 Mean 94.04 89.96 87.95 86.00 %Difference to baseline −4.35% −6.47% −8.55% % Difference to previous−4.35% −2.23% −2.22% p-Value against Baseline 9.17E−14 1.93E−11 9.91E−12

TABLE 8 Profilometery data for untreated areas of the skin of thesubjects Untreated Baseline Week 4 Week 8 Week 12 Mean 93.09 93.00 93.1492.61 % Difference to baseline −0.09% 0.05% −0.51% % Difference toprevious −0.09% 0.15% −0.57% p-Value against Baseline 8.06E−01 7.54E−011.26E−01

CUTOMETER® assessments were performed according to the methods describedin Example 4. CUTOMETER® assessments of skin firmness and elasticityshow a highly statistically significant improvement in both skinfirmness and skin elasticity as shown in the below table for the treatedsite (Table 9). Following 12 weeks of use an improvement of 60.34% wasobserved at the treated site. The untreated control site showed nosignificant change in skin firmness or elasticity at any time-pointduring the trial validating the data (Table 10).

TABLE 9 CUTOMETER ® data for treated areas of the skin of the subjectsTreated Baseline Week 4 Week 8 Week 12 Mean 0.53 0.64 0.73 0.85 %Difference to baseline 20.71% 37.74% 60.34% % Difference to previous20.71% 14.11% 16.41% p-Value against Baseline 2.42E−11 9.25E−16 2.07E−19

TABLE 10 CUTOMETER ® data for untreated areas of the skin of thesubjects Untreated Baseline Week 4 Week 8 Week 12 Mean 0.53 0.53 0.530.53 % Difference to baseline 0.16% −0.02% 0.31% % Difference toprevious 0.16% −0.19% 0.33% p-Value against Baseline 3.96E−05 1.15E−067.97E−05

CHROMAMETER CR300® assessments were performed according to the methodsdescribed in Example 5. CHROMAMETER CR300® assessments of skin tone andcoloration showed no significant lightening of the area around thetreated area at any time-points. No positive statistically improvementwas observed at any time point as shown in the summary tables below(Tables 11 and 12). At week 12 the untreated site showed a minimallystatistical darkening of the test site compared to baseline values.

TABLE 11 CHROMAMETER CR300 ® data for treated areas of the skin of thesubjects Treated Baseline Week 4 Week 8 Week 12 Mean 60.48 90.97 60.0659.14 % Difference to baseline −0.81% 0.69% 2.16% % Difference toprevious −0.81% 1.49% 1.48% p-Value against Baseline 2.15E−01 4.31E−015.13E−02

TABLE 12 CHROMAMETER CR300 ® data for untreated areas of the skin of thesubjects Untreated Baseline Week 4 Week 8 Week 12 Mean 60.66 60.71 60.4259.55 % Difference to baseline −0.07% 0.40% 1.84% % Difference toprevious −0.07% 0.47% 1.45% p-Value against Baseline 8.83E−01 5.23E−011.25E−02

CORNEOMETER® CM825 assessments were performed according to the methodsdescribed in Example 6. CORNEOMETER® CM825 values of skin moisturizationat both the test site and untreated site show no statisticallysignificant hydration under humectant property measurements (Tables 13and 14). A mean rise in moisture content of the skin was observedhowever as this was observed for both the treated and untreated controlsites no efficacious effect of the article can be considered valid.

TABLE 13 CORNEOMETER ® CM825 data for treated areas of the skin of thesubjects Treated Baseline Week 4 Week 8 Week 12 Mean 36.24 43.66 39.6343.35 % Difference to baseline 20.49% 9.36% 19.63% % Difference toprevious 20.49% −9.24% 9.39% p-Value against Baseline 9.17E−02 2.29E−011.02E−01

TABLE 14 CORNEOMETER ® CM825 data for untreated areas of the skin of thesubjects Untreated Baseline Week 4 Week 8 Week 12 Mean 34.51 39.75 38.3344.68 % Difference to baseline 15.15% 11.04% 29.46% % Difference toprevious 15.15% −3.57% 16.59% p-Value against Baseline 2.17E−01 1.39E−015.08E−04

Visual assessments were performed according to the methods described inExample 7. Visual assessments according to the Glogau scale of visibleageing (Table 5) showed a 34.51% reduction in the visible aging scoreobserved for the treated site following 12 weeks of usage (Table 15).The untreated site showed no observable reduction in visible ageingfollowing 12 weeks of usage (Table 15).

TABLE 15 Visual assessment data for treated and for untreated areas ofthe skin of the subjects Treated Untreated Baseline Week 8 Week 12Baseline Week 8 Week 12 Mean 3.09 2.09 2.02 3.09 3.09 3.15 % Difference32.27% 34.51% -0.13% -2.11% to baseline % Difference 32.27% 3.31% -0.13%-1.98% to previous

The test composition of Example 1, Table 1 showed excellent results inreducing wrinkles, increasing firmness of the skin, and increasingelasticity of the skin. The test composition of Example 1, Table 1treated photoaging based on evaluation of the skin of the subject andobserving the following effects anti-wrinkle; visible reduction of finelines and wrinkle; reduction of the appearance of fine lines andwrinkles by about 9% in 12 weeks; skin firming; improvement of skintexture; improvement of skin elasticity by about 60% in 12 weeks;firming the skin by about 38% in 8 weeks.

Although the invention has been described with reference to the aboveexamples, it will be understood that modifications and variations areencompassed within the spirit and scope of the invention.

What is claimed is:
 1. A composition comprising: a) a first anti-acnecompound; b) a second anti-acne compound, wherein each of the first andsecond anti-acne compounds are selected from the group consisting ofazelaic acid, clindamycin, niacinamide, tretinoin, and zinc pyrithione,or a pharmaceutically acceptable salt thereof; and c) an anti-photoagingcompound, wherein the anti-photoaging compound is selected from thegroup consisting of azelaic acid, niacinamide, and ascorbyl phosphate,or a pharmaceutically acceptable salt thereof, wherein the firstanti-acne compound, the second anti-acne compound, and theanti-photoaging compound are three different compounds.
 2. Thecomposition of claim 1, wherein the composition comprises tretinoin. 3.The composition of claim 2, wherein the tretinoin makes up between 0.005and 0.2% of the composition w/w.
 4. The composition of claim 2, whereinthe tretinoin makes up between 0.01 and 0.1% of the composition w/w. 5.A kit comprising: 1) a composition comprising: a) a first anti-acnecompound; b) a second anti-acne compound, wherein each of the first andsecond anti-acne compounds are selected from the group consisting ofazelaic acid, clindamycin, niacinamide and zinc pyrithione, or apharmaceutically acceptable salt thereof; c) an anti-photoagingcompound, wherein the anti-photoaging compound is selected from thegroup consisting of azelaic acid, and niacinamide, or a pharmaceuticallyacceptable salt thereof; and d) a pharmaceutically acceptable vehicle,wherein the first anti-acne compound, the second anti-acne compound, andthe anti-photoaging compound are three different compounds; and 2) asealed container for housing the composition.
 6. The kit of claim 5,wherein the composition comprises clindamycin, zinc pyrithione, andniacinamide.
 7. The kit of claim 5, wherein the composition comprisesclindamycin, niacinamide, and azelaic acid.
 8. The kit of claim 5,wherein the composition comprises clindamycin, zinc pyrithione, andazelaic acid.
 9. The kit of claim 5, wherein the second compositioncomprises niacinamide, zinc pyrithione, and azelaic acid.
 10. Acomposition comprising between 0.005% w/w and 0.3% w/w tretinoin,between 2% w/w and 6% w/w niacinamide, and between 4% to 20% w/w azelaicacid.
 11. A composition comprising between 0.005% w/w and 0.3% w/wtretinoin, between 0.1% w/w and 0.5% w/w zinc pyrithione, and between 4%to 20% w/w azelaic acid.
 12. A composition comprising between 0.005% w/wand 0.3% w/w tretinoin, between 2% w/w and 6% w/w niacinamide, andbetween 0.5% w/w and 1.5% w/w clindamycin.
 13. A method for thetreatment of acne and photoaging in a subject in need thereof comprisingadministering to the skin of the subject a composition selected from thegroup consisting of: a) a composition comprising between 4% w/w and 20%w/w azelaic acid, between 0.01% w/w and 2% w/w zinc pyrithione, andbetween 0.5% w/w and 1.5% w/w clindamycin; b) a composition comprisingbetween 4% w/w and 20% w/w azelaic acid, between 2% w/w and 6% w/wniacinamide, and between 0.01% w/w and 2% w/w zinc pyrithione; c) acomposition comprising between 0.02% w/w and 0.14% w/w tretinoin,between 4% w/w and 20% w/w azelaic acid, and between 0.5% w/w and 1.5%w/w clindamycin; d) a composition comprising between 0.01% w/w and 0.1%w/w tretinoin, between 0.01% w/w and 2% w/w zinc pyrithione, and betweenabout 0.5% w/w and 1.5% w/w clindamycin; e) a composition comprisingbetween 0.1% w/w and 25% w/w azelaic acid, between 2% w/w and 6% w/wniacinamide, and between about 0.5% w/w and 1.5% w/w clindamycin; f) acomposition comprising between 0.005% w/w and 0.3% w/w tretinoin,between 2% w/w and 6% w/w niacinamide, and between 4% to 20% w/w azelaicacid; g) a composition comprising between 0.005% w/w and 0.3% w/wtretinoin, between 0.1% w/w and 0.5% w/w zinc pyrithione, and between 4%to 20% w/w azelaic acid; and h) a composition comprising between 0.005%w/w and 0.3% w/w tretinoin, between 2% w/w and 6% w/w niacinamide, andbetween 0.5% w/w and 1.5% w/w clindamycin.
 14. The method of claim 13,wherein the composition comprises between 4% w/w and 20% w/w azelaicacid, between 0.01% w/w and 2% w/w zinc pyrithione, and between 0.5% w/wand 1.5% w/w clindamycin.
 15. The method of claim 13, wherein thecomposition comprises between 4% w/w and 20% w/w azelaic acid, between2% w/w and 6% w/w niacinamide, and between 0.01% w/w and 2% w/w zincpyrithione.
 16. The method of claim 13, wherein the compositioncomprises between 0.02% w/w and 0.14% w/w tretinoin, between 4% w/w and20% w/w azelaic acid, and between 0.5% w/w and 1.5% w/w clindamycin. 17.The method of claim 13, wherein the composition comprises between 0.01%w/w and 0.1% w/w tretinoin, between 0.01% w/w and 2% w/w zincpyrithione, and between about 0.5% w/w and 1.5% w/w clindamycin.
 18. Themethod of claim 13, wherein the composition comprises between 0.1% w/wand 25% w/w azelaic acid, between 2% w/w and 6% w/w niacinamide, andbetween about 0.5% w/w and 1.5% w/w clindamycin.
 19. The method of claim13, wherein the composition comprises between 0.005% w/w and 0.3% w/wtretinoin, between 2% w/w and 6% w/w niacinamide, and between 4% to 20%w/w azelaic acid.
 20. The method of claim 13, wherein the compositioncomprises between 0.005% w/w and 0.3% w/w tretinoin, between 0.1% w/wand 0.5% w/w zinc pyrithione, and between 4% to 20% w/w azelaic acid.21. The method of claim 13, wherein the composition comprises between0.005% w/w and 0.3% w/w tretinoin, between 2% w/w and 6% w/wniacinamide, and between 0.5% w/w and 1.5% w/w clindamycin.